Recombinant anti-CD4 antibodies for human therapy

Abstract

Chimeric antibodies specific to human CD4 antigen, DNA encoding, pharmaceutical compositions containing and use thereof as therapeutic agents are taught. These chimeric antibodies contain Old World monkey variable sequences and human constant domain sequences, preferably human gamma 1, gamma 4 or mutated forms thereof. These antibodies possess desirable therapeutic properties including low antigenicity, reduced (or absent) T cell depleting activity, good affinity to human CD4 and enhanced stability (in vivo half-life).

The invention claimed is: 
     
       1. A method of treating a patient having a disease, condition or disorder characterized by an increased number of CD4 positive lymphocytes comprising administering a therapeutically effective amount of a chimeric anti-CD4 antibody that comprises heavy and light chain variable regions of an Old World Monkey antibody and human antibody constant regions, wherein said chimeric antibody inhibits CD4-positive dependent T cell responses. 
     
     
       2. The method of  claim 1  wherein said disease, condition or disorder is selected from the group consisting of leukemia, lymphoma, asthma, HIV infection, and transplant rejection, and graft-versus-host disease. 
     
     
       3. The method of  claim 2 , wherein said disease, condition or disorder is transplant rejection or graft-versus-host disease. 
     
     
       4. The method of  claim 1  wherein said disease, condition or disorder is an allergic condition. 
     
     
       5. The method of  claim 4  wherein said allergic condition is asthma. 
     
     
       6. The method of  claim 1  wherein said chimeric anti-CD4 antibody has a human antibody gamma 4 constant region. 
     
     
       7. The method of  claim 1  wherein said anti-CD4 antibody has a human antibody gamma 1 constant region. 
     
     
       8. The method of  claim 6  wherein said gamma 4 constant region comprises at least one mutation selected from the group consisting of:
 substitution of glutamic acid in place of leucine at position 248 (Kabat numbering); and 
 substitution of proline in place of serine at position 241 (Kabat numbering). 
 
     
     
       9. The method of  claim 1  wherein said Old World Monkey heavy and light chain variable regions have polypeptide sequences encoded by the DNA sequences in SEQ ID NO: 3 and SEQ ID NO: 1 respectively. 
     
     
       10. The method of  claim 2 , wherein said disease, condition or disorder is lymphoma. 
     
     
       11. The method of  claim 1  wherein said disease, condition or disorder is an autoimmune or chronic inflammatory disease, condition or disorder. 
     
     
       12. The method of  claim 11 , wherein said autoimmune or chronic inflammatory disease, condition or disorder is selected from the group consisting of Hashimoto's thyroiditis, primary myxoedema, thyrotoxicosis/Graves disease, pernicious anaemia, autoimmune atrophic gastritis, autoimmune carditis, Addison's disease, premature menopause, type I diabetes mellitus, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, male infertility pemphigus vulgaris, pemphigoid, sympathetic ophthalmia, phacogenic uveitis, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis (HBs Ag negative), crptogenic cirrhosis, inflammatory bowel disease syndrome, Sjögren's syndrome, psoriasis, rheumatoid arthritis, dermatomyositis, scleroderma, mixed tissue connective disease, discoid lupus erythematosus, systemic vasculitis, and systemic lupus erythematosus (SLE). 
     
     
       13. The method of  claim 12 , wherein the autoimmune or chronic inflammatory disease, condition or disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, type I-diabetes mellitus, cirrhosis, inflammatory bowel disease, SLE, and multiple sclerosis. 
     
     
       14. The method of  claim 1 , wherein the chimeric anti-CD4 antibody comprises:
 a heavy chain having a polypeptide sequence selected from the group consisting of the gamma 4 heavy chain polypeptide sequence in SEQ ID NO:7, the gamma 4 (E) heavy chain polypeptide sequence in SEQ ID NO:9; and the gamma 4 (PE) heavy chain polypeptide sequence in SEQ ID NO:11; and 
 a light chain having the variable region polypeptide sequence in SEQ ID NO:1 and a constant region polypeptide sequence of a human kappa or lambda light chain. 
 
     
     
       15. The method of  claim 14 , wherein the chimeric anti-CD4 antibody comprises a heavy chain having the gamma 4 heavy chain polypeptide sequence in SEQ ID NO:7. 
     
     
       16. The method of  claim 14 , wherein the chimeric anti-CD4 antibody comprises a heavy chain having the gamma 4 (E) heavy chain polypeptide sequence in SEQ ID NO:9. 
     
     
       17. The method of  claim 14 , wherein the chimeric anti-CD4 antibody comprises a heavy chain having the gamma 4 (PE) heavy chain polypeptide sequence in SEQ ID NO:11. 
     
     
       18. The method of  claim 14 , wherein the chimeric anti-CD4 antibody comprises a light chain having the lambda light chain polypeptide sequence in SEQ ID NO:5.